Myotonic dystrophy (DM or Steinert's disease) is a multisystemic disorder often characterized by muscle degeneration and myotonia or delayed muscle relaxation due to repetitive action potentials in myofibers. Numerous multisystemic symptoms are observed in DM patients, including over 100 biological processes negatively affected in their muscle cells. Manifestations of DM can include heart conduction defects, ocular cataracts, hypogonadism, and nervous system dysfunction. DM patients also often suffer from cardiac conduction defects, smooth muscle involvement, hypersomnia, cataracts, abnormal glucose response, and, in males, premature balding and testicular atrophy. Myotonic dystrophy is the most common muscular dystrophy of adults for which there are no effective therapies.
Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy, affecting about 1 in 8000 people. DM1 is a trinucleotide repeat expansion disorder (TREDs) with (CTG)n step sequences aberrantly expanded in the 3′-untranslated region of the DMPK gene. At the RNA level, the DMPK transcript sequesters splicing regulator proteins, in particular muscleblind-like (MBNL) protein, which results in incorrect splicing of a number of pre-mRNAs, and this gain-of-function is the direct cause of DM1. A drug that binds to CUG repeats, thereby freeing MBNL to regulate splicing of its pre-mRNA targets, could provide a successful therapeutic strategy. Alternatively, binding looped out (CTG)n repeats may inhibit transcription of the expanded region or even reduce the expansion during repair or replication. Accordingly, agents and therapeutic agents that selectively bind MBNL protein and treat myotonic dystrophy are needed to bolster the clinical therapy of these disorders.